In the past 25 years, little improvement has been made in patient survival after a diagnosis of glioblastoma multiforme (GBM). The robust induction of angiogenesis, extreme resistance to radiation, and a highly aggressive, invasive phenotype make GBM one of the most lethal and difficult human cancers to treat. Recently, a mesenchymal subtype of GBMs has been identified that displays the most infiltrative behavior, is the most resistant to standard therapies, and expresses markers, such as a secreted protein YKL-40, which correlate with the worst patient prognosis. We have identified that two proinflammatory cytokines, interleukin-1? (IL-1?) and oncostatin M (OSM), are specifically overexpressed in patients with mesenchymal GBM. Our data indicates that IL-1? and OSM synergize to support GBM progression through a novel RelB/p50-canonical pathway, which to date has only been proposed to function in cells expressing high levels of RelB. Our preliminary studies have identified two groups of RelB/p50-dependent genes in GBM cells and astrocytes: conserved genes (activated in both GBM and astrocytes) and aberrantly-activated genes (activated in GBM but suppressed in astrocytes). The conserved genes include markers of the mesenchymal GBM subtype and intriguing novel genes postulated to regulate GBM progression. The aberrantly activated genes encode many cytokines, including IL-1, which suggests the existence of RelB-driven feedforward cytokine loop fueling chronic inflammation in GBM. Importantly, the aberrantly-activated genes have previously been shown to undergo RelB-dependent reprograming by epigenetic silencing in macrophages, which requires histone deacetylase SIRT1. Our preliminary studies have found that one allele of the sirt1 gene is deleted in 75% of GBM tumors, which may explain the lack of RelB-dependent epigenetic silencing in GBM. Thus, we hypothesize that RelB/p50 activation drives gene expression programs which induced both chronic inflammation and GBM aggressiveness.